Affinage

SFTPC

Surfactant protein C · UniProt P11686

Length
197 aa
Mass
21.0 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SFTPC encodes proSP-C, a type II transmembrane proprotein synthesized exclusively in alveolar type II cells, where it is anchored by the hydrophobic mature SP-C segment that serves as both signal sequence and membrane anchor and is required for downstream processing and transport (PMID:1859376, PMID:7519606). Following membrane integration, the 21-kDa propeptide is processed in compartments distal to the trans-Golgi network through a 16-kDa lamellar-body intermediate to the mature 4.2-kDa peptide (PMID:7519606), with sorting driven by transmembrane-domain-mediated homo-oligomerization of proSP-C monomers (PMID:11907042). Mature SP-C is dually palmitoylated on adjacent cysteines (PMID:1872406) and adopts a predominantly alpha-helical transmembrane fold (PMID:1911771); at the air-liquid interface it acts as a 'hydrophobic lever' that reorients to facilitate spreading and ordered packing of phospholipids (PMID:9199811), promotes vesicle binding and lipid insertion into monolayers (PMID:1932022, PMID:1868098), and stimulates cellular lipid uptake/endocytosis (PMID:8772529). Palmitoylation is critical for surfactant films to reach very low surface tensions during rapid compression in cooperation with SP-B (PMID:21081071), and loss of SP-C in vivo destabilizes surfactant films at low lung volumes and produces progressive emphysematous, inflammatory lung disease (PMID:11344267, PMID:12519727). Transcription of SFTPC is driven by TTF-1/Nkx2.1 acting on the proximal promoter (PMID:10781423) and is repressed when Foxp2 binds Nkx2.1 to block its DNA binding, providing a mechanism for SP-C downregulation during AT2-to-AT1 transition (PMID:18239190). Disease-associated SFTPC mutations cause proteostatic catastrophe in AT2 cells: the I73T mutation in the C-terminal propeptide misroutes proSP-C to the endosomal network and plasma membrane and imposes a late block in macroautophagy and mitophagy (PMID:15293602, PMID:25344067), while BRICHOS-domain mutations cause ER retention, aggregate formation, IRE1/XBP-1-dependent UPR, proteasome inhibition, NF-κB-driven cytokine production, and apoptosis (PMID:17586700, PMID:30721158). Knockin mouse and patient iPSC-derived AT2 models establish that expression of mutant SP-C in AT2 cells is causally upstream of alveolitis, proteostatic and metabolic dysfunction, and TGF-β1-driven lung fibrosis (PMID:29920187, PMID:30721158, PMID:34469722).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 1991 High

    Established how proSP-C is inserted into membranes and that correct topology gates all subsequent processing, defining the protein's biosynthetic starting point.

    Evidence In vitro biosynthesis and membrane topology analysis showing signal-peptidase-independent integration via the hydrophobic mature domain

    PMID:1859376

    Open questions at the time
    • Did not identify the protease(s) performing downstream cleavage
    • Translocon machinery mediating insertion not defined
  2. 1991 High

    Defined the biophysical activity of mature SP-C, showing it inserts lipids into interfacial monolayers and forms ordered alpha-helical films, the basis of its surfactant function.

    Evidence Langmuir monolayer insertion assays, FT-IR/ESR spectroscopy, and dynamic surface measurements with reconstituted SP-C

    PMID:1868098 PMID:1911771 PMID:1932022 PMID:7696261

    Open questions at the time
    • In vitro reconstitution does not establish stoichiometry in native lamellar bodies
    • Functional cooperation with SP-B only partially dissected here
  3. 1991 High

    Identified the dual S-palmitoylation of SP-C cysteines, a covalent modification later shown to be functionally critical.

    Evidence Fast atom bombardment mass spectrometry plus in vitro acylation with palmitoyl-CoA across three species

    PMID:1872406

    Open questions at the time
    • Acyltransferase responsible for palmitoylation not identified
    • Functional consequence not addressed in this study
  4. 1991 Medium

    Localized SP-C expression to distal respiratory epithelium and its precursors, establishing AT2-cell-restricted production preceding overt differentiation.

    Evidence In situ hybridization and ribonuclease protection in fetal rabbit lung

    PMID:1540386

    Open questions at the time
    • Single developmental model (rabbit)
    • Transcriptional drivers of restriction not addressed here
  5. 1992 High

    Mapped the intracellular processing pathway from 21-kDa propeptide through a 16-kDa lamellar-body intermediate to mature secreted peptide.

    Evidence Subcellular fractionation, metabolic labeling, epitope-specific antibodies, and brefeldin A inhibition in perfused rat lung

    PMID:7519606

    Open questions at the time
    • Specific proteases generating each intermediate not identified
    • Kinetics of palmitoylation relative to cleavage steps unresolved
  6. 1992 High

    Distinguished SP-C from SP-B functionally by showing SP-C does not mediate inter-vesicle lipid mixing and alters monolayer lipid domain packing, sharpening the division of labor between the two hydrophobic surfactant proteins.

    Evidence Pyrene excimer lipid-mixing assay and epifluorescence microscopy of reconstituted monolayers

    PMID:1390835 PMID:1420867

    Open questions at the time
    • Negative result defines what SP-C does not do, not full positive mechanism
    • Behavior in native multi-component surfactant not tested
  7. 1993 High

    Showed SP-C transcription is glucocorticoid-inducible via a secondary, protein-synthesis-dependent mechanism distinct from SP-B regulation.

    Evidence Nuclear run-on, cycloheximide/actinomycin D, and mRNA stability assays in human fetal lung explants

    PMID:8427712

    Open questions at the time
    • Identity of the labile intermediary transcription factor not determined
    • Glucocorticoid receptor binding sites not mapped
  8. 1993 Medium

    Characterized temperature- and lipid-phase-dependent SP-C self-association in bilayers, implicating protein oligomerization in surfactant film organization.

    Evidence FRET and fluorescence anisotropy with labeled SP-C in reconstituted vesicles

    PMID:8373758

    Open questions at the time
    • Physiological relevance of gel-phase-dependent aggregation unclear
    • Single-lab biophysical observation
  9. 2000 High

    Identified TTF-1/Nkx2.1 as a direct transactivator of the SP-C promoter and mapped proximal and distal regulatory elements.

    Evidence Transgenic mice with serial promoter deletions plus cotransfection transactivation assays

    PMID:10781423

    Open questions at the time
    • Co-regulators acting at distal enhancers not identified
    • Mechanism restricting expression to AT2 cells incompletely defined
  10. 2001 High

    Defined the in vivo physiological role of SP-C by showing knockout mice have unstable surfactant films at low lung volumes.

    Evidence SP-C knockout mice analyzed by captive bubble surfactometry and lung mechanics

    PMID:11344267

    Open questions at the time
    • Did not address progressive disease phenotype
    • Compensation by other surfactant components not quantified
  11. 2003 High

    Demonstrated SP-C deficiency causes progressive inflammatory lung disease with emphysema, MMP upregulation, and myofibroblast transformation, extending its role beyond acute surface activity.

    Evidence SP-C knockout mouse histology, lung mechanics, MMP activity, and immunohistochemistry

    PMID:12519727

    Open questions at the time
    • Mechanistic link from surfactant instability to MMP induction not established
    • Genetic background dependence noted but not fully resolved
  12. 2002 High

    Established that proSP-C trafficking depends on transmembrane-domain-mediated homo-oligomerization, with wild-type protein able to rescue trafficking-deficient but not folding-deficient mutants.

    Evidence GFP-construct fluorescence microscopy, chemical cross-linking, and co-transfection rescue in A549 cells

    PMID:11907042

    Open questions at the time
    • Sorting receptors/adaptors mediating routing not identified
    • Distinction between folding and trafficking mutants mechanistically incomplete
  13. 2003 High

    Showed deacylated SP-C undergoes reversible pH-dependent alpha-helix-to-amyloid conversion, linking palmitoylation loss to aberrant beta-fibril structure incompatible with interfacial activity.

    Evidence ATR-FTIR and PM-IRRAS with pH manipulation and interface studies

    PMID:14507705

    Open questions at the time
    • In vitro deacylated peptide may not recapitulate cellular misfolding
    • Relationship to disease-mutant aggregates not directly tested
  14. 2004 High

    Identified the de novo I73T mutation as a cause of aberrant proSP-C trafficking to early endosomes with abnormal palmitoylation, connecting a specific human mutation to mistrafficking.

    Evidence GFP-fusion trafficking in A549 cells with patient biopsy correlation

    PMID:15293602

    Open questions at the time
    • Downstream cellular toxicity not characterized in this study
    • In vivo consequences not yet established
  15. 2006 Medium

    Showed misfolded SP-C(Deltaexon4) drives chronic NF-κB-dependent adaptation to ER stress and sensitizes cells to viral injury, linking mutant SP-C to inflammatory signaling.

    Evidence Stable cell lines with NF-κB inhibition, RSV challenge, and UPR marker analysis

    PMID:16449190

    Open questions at the time
    • Cell-line model rather than AT2 cells
    • Single lab; in vivo relevance not tested here
  16. 2006 Medium

    Demonstrated that oxidative modification of SP-C reduces palmitoylation and impairs surfactant function, identifying ROS as a mechanism of acquired SP-C dysfunction.

    Evidence HOCl/Fenton oxidation of surfactant with reconstitution and surface activity measurements

    PMID:16443649

    Open questions at the time
    • In vivo oxidative inactivation not demonstrated
    • Single-lab reconstitution study
  17. 2007 High

    Defined a convergent cellular toxicity program for BRICHOS-domain mutants involving aggregation, IRE1/XBP-1 UPR, proteasome inhibition, and mitochondrial apoptosis.

    Evidence Transient transfection of two BRICHOS mutants in A549 and HEK-293 cells with aggregate, UPR, proteasome, and caspase assays

    PMID:17586700

    Open questions at the time
    • Transient overexpression may amplify toxicity
    • Not validated in primary AT2 cells in this study
  18. 2010 High

    Separated palmitoylation-dependent from -independent SP-C functions, showing palmitoylation is required for cholesterol-containing films to reach very low surface tensions but not for equilibrium adsorption.

    Evidence Captive bubble surfactometry comparing native palmitoylated and recombinant non-palmitoylated SP-C

    PMID:21081071

    Open questions at the time
    • Molecular basis of cooperation with SP-B at low surface tension not fully resolved
    • Cholesterol dependence mechanism incompletely defined
  19. 2008 High

    Identified Foxp2-Nkx2.1 antagonism as a transcriptional brake on SP-C, providing a mechanism for its downregulation during AT2-to-AT1 transition.

    Evidence Co-IP, mammalian two-hybrid, EMSA, ChIP, and luciferase reporter assays in MLE-15 cells

    PMID:18239190

    Open questions at the time
    • In vivo requirement for Foxp2 in AT1 differentiation not tested here
    • Additional Nkx2.1 partners not assessed
  20. 2013 Medium

    Showed that distinct SFTPC mutations partition into ER-arrested versus lamellar-body-trafficking classes with differing aggregation behavior, refining genotype-cell-biology relationships.

    Evidence Stable A549 transfection of multiple mutants with Congo red staining and ER stress markers

    PMID:23701443

    Open questions at the time
    • No ER stress detected in this system, conflicting with other models
    • Single-lab stable-line comparison
  21. 2013 Medium

    Showed SP-C and SP-B form proteolipid pores with lipid-dependent ion selectivity, suggesting a membrane-permeabilizing activity beyond surface tension reduction.

    Evidence Planar lipid bilayer electrophysiology with reconstituted SP-C/SP-B

    PMID:23332067

    Open questions at the time
    • Not independently replicated
    • Physiological role of the channel activity unknown
  22. 2014 High

    Demonstrated that I73T mistrafficking imposes a distal block in macroautophagy and mitophagy, mechanistically linking the mutation to proteostatic and mitochondrial dysfunction.

    Evidence Stable cell lines, EM, autophagy flux studies, substrate degradation reporters, and mitochondrial potential assays with patient biopsy correlation

    PMID:25344067

    Open questions at the time
    • Molecular trigger of the autophagy block not pinpointed
    • Cell-line model rather than native AT2 cells
  23. 2018 High

    Established in vivo that inducible I73T expression in AT2 cells is causally upstream of alveolitis and TGF-β1-driven fibrosis, providing proof of causality for SFTPC-driven lung disease.

    Evidence Tamoxifen-inducible knockin mouse with BAL cytokine, histology, collagen, and lung mechanics analysis

    PMID:29920187

    Open questions at the time
    • Cell-autonomous versus paracrine contributions to fibrosis not fully separated
    • Therapeutic reversibility not addressed
  24. 2018 Medium

    Resolved how SP-C and SP-B physically interact, demonstrating compartmentalized homo- and hetero-oligomers in native surfactant membranes.

    Evidence Steady-state and time-resolved homo-/hetero-FRET with labeled proteins in reconstituted vesicles

    PMID:29700110

    Open questions at the time
    • Functional consequence of hetero-oligomer compartmentalization not directly tested
    • Single-lab spectroscopic study
  25. 2019 High

    Showed a BRICHOS C121G mutation causes ER retention, NF-κB-driven cytokine production, and spontaneous fibrosis, with fetal expression causing fatal gain-of-function, distinguishing BRICHOS from I73T pathobiology.

    Evidence SftpcC121G knockin mouse with ER stress assays, BAL proteomics, and patient cohort correlation

    PMID:30721158

    Open questions at the time
    • Mechanistic link from ER stress to fibrotic remodeling not fully detailed
    • Why fetal versus postnatal expression differs in severity unresolved
  26. 2021 High

    Recapitulated I73T pathobiology in patient iPSC-derived AT2 cells with isogenic correction, linking misprocessing to diminished progenitor capacity, metabolic reprogramming, and NF-κB activation, and revealing drug-aggravated phenotypes.

    Evidence iPSC-derived AT2 cells with syngeneic gene-corrected controls, trafficking and metabolic profiling, NF-κB reporters, and pharmacology

    PMID:34469722

    Open questions at the time
    • In vitro AT2 cells may not capture full alveolar niche
    • Therapeutic implications of hydroxychloroquine aggravation not clinically validated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The specific protease(s) that generate the SP-C processing intermediates and the palmitoyltransferase modifying SP-C cysteines remain unidentified, as does the trafficking adaptor machinery that routes proSP-C and how disease mutations subvert it.
  • No enzyme identified for proteolytic maturation
  • Palmitoyltransferase for SP-C unknown
  • Sorting receptors for proSP-C trafficking undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 6 GO:0005198 structural molecule activity 3
Localization
GO:0005783 endoplasmic reticulum 3 GO:0031410 cytoplasmic vesicle 3 GO:0005576 extracellular region 2 GO:0005768 endosome 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-1643685 Disease 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-9612973 Autophagy 1
Partners
FOXP2NKX2-1SFTPB

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 The SP-C precursor (proSP-C) is a type II transmembrane protein: it is anchored in the membrane by the hydrophobic domain comprising the mature SP-C sequence, with the N-terminus remaining in the cytoplasm. Membrane integration occurs in a signal-peptidase-independent manner, and the hydrophobic domain acts as both signal sequence and membrane-anchoring domain. Correct membrane insertion is a prerequisite for further processing and intracellular transport. In vitro biosynthesis/translation assay, topology analysis of integral membrane protein The Biochemical journal High 1859376
1991 SP-C (and SP-B) promote lipid insertion into phospholipid monolayers from vesicles. SP-B and SP-C directly bind vesicles to the monolayer; this vesicle binding and insertion requires close contacts between monolayer and vesicles. Both proteins form stable alpha-helical monolayers oriented parallel to the interface. SP-C has approximately 4-fold lower vesicle-binding capacity than SP-B by weight. Langmuir monolayer lipid insertion assay, Wilhelmy plate method, monolayer surface property measurements Biochemistry High 1868098 1932022
1991 SP-C adopts approximately 60% alpha-helical secondary structure in lipid vesicles, with the helical segments oriented at approximately 24 degrees to the bilayer normal (suggesting transmembrane orientation). SP-C (1 mol%) markedly reduces viscance and increases elasticity of surface films, indicating it facilitates phospholipid spreading. FT-IR spectroscopy, dynamic surface measurements, deuterium exchange Biochemistry High 1911771
1991 SP-C (and SP-B) reduce mobility of phospholipid acyl chains in DPPC and DPPG bilayers as measured by ESR spectroscopy. SP-C has greater effects on phospholipid bilayer ordering than SP-B. The effect saturates at ~30% (w/w) protein/lipid for SP-C in DPPC. SP-C does not show selectivity for negatively charged phospholipids, unlike SP-B. Electron spin resonance (ESR) spectroscopy of spin-labeled phospholipids in reconstituted multilamellar vesicles Biochemistry High 7696261
1991 SP-C cysteines (C4 and C5) are modified by thioester-linked palmitoyl chains in human, canine, and bovine SP-C. This palmitoylation was confirmed by fast atom bombardment mass spectrometry and by acylation of recombinant SP-C with palmitoyl-CoA followed by release with DTT. Fast atom bombardment mass spectrometry, in vitro acylation with palmitoyl-CoA, chemical release with DTT The American journal of physiology High 1872406
1991 SP-C mRNA is restricted to distal respiratory epithelium (type II alveolar cells and their precursors) and is not expressed in bronchiolar epithelium at any stage, as determined by in situ hybridization in fetal rabbit lung. SP-C mRNA appears in prealveolar epithelial cells approximately 7 days before differentiated type II cells appear. In situ hybridization, ribonuclease protection assay American journal of respiratory cell and molecular biology Medium 1540386
1992 SP-C alters the packing arrangement of DPPC in monolayers, causing formation of many more, smaller condensed lipid domains compared to pure DPPC monolayers, as visualized by epifluorescence microscopy. Epifluorescence microscopy of monolayers, surface balance Biophysical journal Medium 1420867
1992 Lipid mixing between vesicles is mediated by SP-B but not by SP-C. SP-C at up to 1 mol% was unable to induce lipid mixing between vesicles at 37°C, whereas SP-B induced lipid mixing in a concentration-dependent manner enhanced by negatively charged phospholipids and divalent cations. Pyrene-labeled PC fluorescence excimer/monomer assay of lipid mixing between vesicles Biochimica et biophysica acta High 1390835
1992 SP-C is synthesized exclusively in type II cells as a 21-kDa propeptide (proSP-C). Processing occurs intracellularly in subcellular compartments distal to the trans-Golgi network: a 21-kDa form is found in microsomes, a 16-kDa intermediate in lamellar bodies, and mature SP-C is secreted. Processing is completely blocked by brefeldin A. Immunocytochemistry, Western blot of subcellular fractions, [35S] metabolic labeling with immunoprecipitation, brefeldin A inhibition in perfused rat lung The Journal of biological chemistry High 7519606
1992 A dimeric form of SP-C ([SP-C]2) exists that lacks palmitoylation at the cysteine residues. This dimer exhibits predominantly beta-sheet secondary structure (by FT-IR), in contrast to the alpha-helical monomeric form. The dimer has surface tension-lowering properties distinct from monomeric SP-C. SDS-PAGE, FT-IR spectroscopy, chemical analysis of acylation, surfactometry Chemistry and physics of lipids Medium 1486663
1993 SP-C self-associates in lipid vesicles in a temperature- and lipid phase-dependent manner, with more than 70% of SP-C in aggregated form below 37°C in DPPC/DPPG vesicles. Self-association decreases above 42°C and requires at least some gel-phase lipids. Fluorescence energy transfer (FRET) using NBD- and EITC-labeled SP-C, fluorescence anisotropy Biochemistry Medium 8373758
1994 ProSP-C is localized exclusively in type II alveolar cells. Subcellular fractionation identifies a 21-kDa proSP-C in microsomes and a 16-kDa form in lamellar bodies, while mature SP-C is not detected in precursor fractions. N-terminal propeptide sequences are detected in lamellar bodies, providing a timeline for the processing intermediates. Immunocytochemistry with epitope-specific antipeptide antibodies, Western blot of subcellular fractions The Journal of biological chemistry High 7519606
1997 SP-C helix tilt angle changes from ~24° to the bilayer normal in lipid bilayers to ~70° in mixed DPPC/SP-C monolayers at the air/water interface, as determined by IRRAS. SP-C acts as a 'hydrophobic lever' by maximizing interactions with lipid acyl chains while permitting ordered lipid packing, providing a molecular mechanism for protein-aided spreading of ordered lipids. External infrared reflection-absorption spectroscopy (IRRAS) of monolayers at the air/water interface Biophysical journal High 9199811
2001 SP-C-deficient mice show decreased surfactant stability at low lung volumes (captive bubble assay), and abnormalities in lung hysteresivity at low positive end-expiratory pressures, demonstrating that SP-C plays a role in stabilization of surfactant films at low lung volumes. SP-C knockout mice, captive bubble surfactometry, lung mechanics (pressure-volume, forced oscillatory dynamics) Proceedings of the National Academy of Sciences of the United States of America High 11344267
2002 SP-C sorting/trafficking involves homomeric oligomerization of proSP-C monomers mediated by the mature SP-C transmembrane domain. Co-transfection of wild-type proSP-C rescues trafficking of mutant proSP-C lacking N-terminal targeting signals, but not of a folding mutant. Chemical cross-linking demonstrates multimeric forms of proSP-C. Fluorescence microscopy of GFP-tagged constructs in transfected A549 cells, chemical cross-linking with bismaleimidohexane, co-transfection rescue assays, colocalization with endosomal markers The Journal of biological chemistry High 11907042
2003 SP-C-deficient mice develop progressive pulmonary disorder with emphysema, monocytic infiltrates, type II cell dysplasia, increased MMP-2 and MMP-9 in alveolar macrophages, and myofibroblast transformation. Absence of SP-C causes severe interstitial pneumonitis with emphysematous mechanics. SP-C knockout mouse model, lung mechanics, histology, immunohistochemistry, Western blot, MMP activity assay The Journal of biological chemistry High 12519727
2003 Deacylated SP-C (dSP-C) transforms from alpha-helical to amyloid fibril (beta-strand) structure via a pH-dependent mechanism: alpha-helix at low pH converts to amyloid-like structure at neutral pH in solution, and this transformation is reversible. The beta-fibril form does not associate with air-water interfaces. Infrared spectroscopy (ATR-FTIR, PM-IRRAS), pH manipulation studies Biophysical journal High 14507705
2004 A de novo SFTPC missense mutation (I73T) in the C-terminal propeptide causes aberrant trafficking of mutant proSP-C to early endosomes (rather than normal routing), with abnormal palmitoylation and secretion. Wild-type proSP-C traffics normally to lamellar body-like vesicles in A549 cells. GFP-fusion protein trafficking in transfected A549 cells, immunohistochemistry, Western blot, ultrastructural analysis The European respiratory journal High 15293602
2006 Stably transfected cells expressing misfolded SP-C(Deltaexon4) adapt to chronic ER stress via an NF-κB-dependent pathway. Upon respiratory syncytial virus infection, cells expressing mutant SP-C showed enhanced cytotoxicity, accumulation of mutant proprotein, pronounced UPR activation, and cell death. Stable transfection in cell lines, NF-κB inhibition, RSV infection, cell viability assays, Western blot for UPR markers The Journal of cell biology Medium 16449190
2007 BRICHOS domain SP-C mutants (hSP-C(Deltaexon4) and hSP-C(L188Q)) cause common cellular dysfunction pathways: increased insoluble aggregate formation, IRE1-dependent XBP-1 splicing (UPR activation), proteasome inhibition, mitochondrial cytochrome c release, and activation of caspase-4 and caspase-3 leading to apoptosis. Transient transfection in A549 and HEK-293 GFP(u)-1 cells, insoluble aggregate assay, XBP-1 splicing assay, proteasome activity assay, cytochrome c release, caspase activity assays American journal of physiology. Lung cellular and molecular physiology High 17586700
2008 Foxp2 directly interacts with the homeodomain transcription factor Nkx2.1 and inhibits Nkx2.1-mediated transcription of SP-C. Foxp2 attenuates Nkx2.1 DNA binding to the SP-C promoter dose-dependently. This interaction provides a mechanism for down-regulation of SP-C during AT2-to-AT1 cell transition. Co-immunoprecipitation, mammalian two-hybrid assay, electrophoretic mobility shift assay, chromatin immunoprecipitation, luciferase reporter assays in MLE-15 cells American journal of respiratory cell and molecular biology High 18239190
2010 Palmitoylation of SP-C is critical for cholesterol-containing surfactant films to reach very low surface tensions (≤1 mN/m) at the highest compression rates in cooperation with SP-B. Palmitoylation is not required for equilibrium adsorption to ~22 mN/m. The ability to facilitate phospholipid reinsertion during expansion was not impaired to the same extent in the absence of palmitoylation, suggesting palmitoylation-dependent and -independent functions. Captive bubble surfactometry comparing native palmitoylated SP-C vs. recombinant non-palmitoylated SP-C in lipid films Biophysical journal High 21081071
2013 SP-C (and SP-B) induce formation of proteolipid pores/channels in planar lipid membranes. Channel-like structures with a range of conductance states (pS to nS) are detected. Ionic selectivity of the pores depends on lipid composition: anionic selectivity in zwitterionic membranes switches to cationic selectivity in negatively charged lipid membranes. Electrophysiological measurements (planar lipid bilayer patch clamp) with reconstituted SP-C and SP-B/lipid mixtures Biophysical journal Medium 23332067
2014 The SP-C I73T mutant dissociates from normal ABCA3-positive lamellar body trafficking and instead colocalizes with the endosomal network and plasma membrane. SP-C(I73T) induces a late block in macroautophagy (distal block in autophagic vacuole maturation), evidenced by increased LC3, p62, and Rab7 expression, impaired degradation of an aggregation-prone substrate, and disrupted mitophagy with decreased mitochondrial membrane potential. Fluorescence microscopy of stably transfected cell lines, transmission electron microscopy, Western blot for autophagy markers, autophagic flux studies with bafilomycin A1 and rapamycin, huntingtin reporter degradation assay, mitochondrial membrane potential assay American journal of physiology. Lung cellular and molecular physiology High 25344067
2018 Induced expression of the IPF-associated SP-C I73T mutation (knockin mouse) causes misprocessed proSP-C accumulation, AT2 cell dysfunction, diffuse parenchymal lung injury, monocyte infiltration, polycellular alveolitis, and subsequent TGF-β1-driven collagen deposition and lung fibrosis. This establishes that mutant SP-C expression in AT2 cells is causally upstream of lung fibrosis. Tamoxifen-inducible knockin mouse model, bronchoalveolar lavage cytokine measurement, histology, collagen quantification, lung mechanics, AT2 cell mRNA analysis The Journal of clinical investigation High 29920187
2019 A BRICHOS domain SP-C mutation (C121G) causes ER retention of proSP-C, AT2 cell ER stress, and cytokine production (NF-κB pathway activation), leading to alveolitis and subsequent spontaneous pulmonary fibrosis. The C121G mutation induces ER stress in vitro, and fetal expression causes toxic gain-of-function with fatal postnatal respiratory failure from disrupted lung morphogenesis. Knockin mouse model (SftpcC121G), ER stress assays, proteomic screen of BAL fluid, lung function testing, histology JCI insight High 30721158
2021 Patient-specific iPSC-derived AT2 cells (iAEC2s) carrying the SFTPC I73T mutation accumulate misprocessed and mistrafficked pro-SFTPC protein, exhibit diminished progenitor capacity, perturbed proteostasis, altered bioenergetic programs, time-dependent metabolic reprogramming, and NF-κB pathway activation. Hydroxychloroquine treatment aggravates these perturbations. Patient-specific iPSC differentiation into AT2 cells, syngeneic gene-corrected controls, protein trafficking assays, metabolic profiling, NF-κB reporter assays, pharmacological treatment Cell reports High 34469722
1993 Glucocorticoid regulation of SP-C is mechanistically distinct from SP-B: SP-C induction by dexamethasone requires ongoing protein synthesis (blocked by cycloheximide), involves increased transcription rate without change in mRNA stability, and is a secondary response requiring a labile transcription factor. SP-B induction is a primary response with both increased transcription and mRNA stabilization. Human fetal lung explant culture, nuclear run-on transcription assay, cycloheximide and actinomycin D treatment, [3H]uridine label-chase for mRNA stability American journal of respiratory cell and molecular biology High 8427712
2000 The thyroid transcription factor TTF-1 (Nkx2.1) transactivates the human SP-C gene through cis-active sites within -215 bp of the SP-C promoter. Sequences between -3.7 kb and -1.9 kb contain enhancer elements; deletion of -1,910 to -215 bp abolishes ectopic bronchiolar expression. Transgenic mice with deletion constructs, tissue CAT assays, in situ hybridization, cotransfection with TTF-1 expression plasmid American journal of physiology. Lung cellular and molecular physiology High 10781423
1996 SP-C incorporates in SP-C-containing lipid vesicles markedly stimulates binding to cell membranes (at 4°C) and endocytosis of lipids (at 37°C) in rat type II cells and MLE-12 cells. SP-C enhances lipid uptake in multiple cell types including non-pulmonary NIH 3T3 cells; SP-B decreased the amount of lipid uptake stimulated by SP-C. Fluorescently labeled lipid vesicle binding and endocytosis assay in rat type II cells and MLE-12 cells at 4°C and 37°C The American journal of physiology Medium 8772529
2006 Reactive oxygen species oxidation of surfactant decreases SP-C palmitoylation and impairs surfactant function. Reconstitution experiments show that protein oxidation (particularly SP-C modification) is more deleterious to surfactant function than lipid oxidation; addition of native SP-B can improve samples containing oxidized SP-C but not vice versa. Oxidation of bovine lipid extract surfactant (BLES) with HOCl/Fenton reaction, Western blot, reconstitution experiments with isolated oxidized proteins, surface activity measurements Biophysical journal Medium 16443649
2018 SP-C and SP-B form homo-oligomers and hetero-oligomers in surfactant membranes. SP-C at under-stoichiometric amounts increases SP-B fluorescence emission and induces conformational changes in SP-B complexes, while over-stoichiometric SP-B quenches SP-C. Time-resolved FRET confirms distinct protein aggregation behaviors. The two proteins are compartmentalized in full surfactant membranes but not in pure POPC vesicles. Fluorescence quenching, homo-FRET, hetero-FRET (steady-state and time-resolved), fluorescence polarization of BODIPY- and Marina Blue-labeled proteins in reconstituted vesicles The Journal of biological chemistry Medium 29700110
2013 Different SFTPC mutations have distinct consequences for proSP-C trafficking: mutations p.I73T, p.L110R, p.A116D, and p.L188Q produce aberrant proSP-C that partially traffics to lamellar bodies, while p.P30L and p.P115L are arrested in the ER. Except for p.I73T, all mutations lead to Congo red-positive intracellular aggregates. Enhanced ER stress was not detected in stably transfected cells with any of these mutations. Stable transfection of A549 cells, Western blot, immunofluorescence, Congo red staining for aggregates, ER stress markers European journal of clinical investigation Medium 23701443

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Transcriptional elements from the human SP-C gene direct expression in the primordial respiratory epithelium of transgenic mice. Developmental biology 270 8462742
2001 Altered stability of pulmonary surfactant in SP-C-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 232 11344267
2018 Expression of mutant Sftpc in murine alveolar epithelia drives spontaneous lung fibrosis. The Journal of clinical investigation 191 29920187
1996 Arrested lung morphogenesis in transgenic mice bearing an SP-C-TGF-beta 1 chimeric gene. Developmental biology 186 8626028
1991 Characterization of lipid insertion into monomolecular layers mediated by lung surfactant proteins SP-B and SP-C. Biochemistry 179 1932022
2003 Pneumonitis and emphysema in sp-C gene targeted mice. The Journal of biological chemistry 167 12519727
2004 Alterations in SP-B and SP-C expression in neonatal lung disease. Annual review of physiology 160 14977415
1991 Genetic element from human surfactant protein SP-C gene confers bronchiolar-alveolar cell specificity in transgenic mice. The American journal of physiology 151 1928370
1991 Interaction of lipid vesicles with monomolecular layers containing lung surfactant proteins SP-B or SP-C. Biochemistry 139 1868098
2001 Effects of lung surfactant proteins, SP-B and SP-C, and palmitic acid on monolayer stability. Biophysical journal 130 11325728
1995 Interactions of hydrophobic lung surfactant proteins SP-B and SP-C with dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylglycerol bilayers studied by electron spin resonance spectroscopy. Biochemistry 127 7696261
2004 Interstitial lung disease in a baby with a de novo mutation in the SFTPC gene. The European respiratory journal 126 15293602
1994 Temporal-spatial distribution of SP-B and SP-C proteins and mRNAs in developing respiratory epithelium of human lung. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 121 8064126
1991 Fourier transform infrared studies of secondary structure and orientation of pulmonary surfactant SP-C and its effect on the dynamic surface properties of phospholipids. Biochemistry 119 1911771
2019 An SFTPC BRICHOS mutant links epithelial ER stress and spontaneous lung fibrosis. JCI insight 115 30721158
1994 Localization, synthesis, and processing of surfactant protein SP-C in rat lung analyzed by epitope-specific antipeptide antibodies. The Journal of biological chemistry 111 7519606
2007 Misfolded BRICHOS SP-C mutant proteins induce apoptosis via caspase-4- and cytochrome c-related mechanisms. American journal of physiology. Lung cellular and molecular physiology 105 17586700
2010 Combined and independent action of proteins SP-B and SP-C in the surface behavior and mechanical stability of pulmonary surfactant films. Biophysical journal 104 21081077
1993 Solubility of hydrophobic surfactant proteins in organic solvent/water mixtures. Structural studies on SP-B and SP-C in aqueous organic solvents and lipids. Biochimica et biophysica acta 102 8323965
2021 Patient-specific iPSCs carrying an SFTPC mutation reveal the intrinsic alveolar epithelial dysfunction at the inception of interstitial lung disease. Cell reports 100 34469722
1998 Lung function in premature lambs and rabbits treated with a recombinant SP-C surfactant. American journal of respiratory and critical care medicine 100 9476872
1997 Structure and orientation of lung surfactant SP-C and L-alpha-dipalmitoylphosphatidylcholine in aqueous monolayers. Biophysical journal 97 9199811
2007 Heterozygosity for ABCA3 mutations modifies the severity of lung disease associated with a surfactant protein C gene (SFTPC) mutation. Pediatric research 95 17597647
1990 Structure and expression of the pulmonary surfactant protein SP-C gene in the mouse. The Journal of biological chemistry 95 2254341
2004 Mutation of SFTPC in infantile pulmonary alveolar proteinosis with or without fibrosing lung disease. American journal of medical genetics. Part A 94 15039969
1992 Pulmonary surfactant protein SP-C causes packing rearrangements of dipalmitoylphosphatidylcholine in spread monolayers. Biophysical journal 92 1420867
1988 Two SP-C genes encoding human pulmonary surfactant proteolipid. The Journal of biological chemistry 92 2839484
2006 Adaptation and increased susceptibility to infection associated with constitutive expression of misfolded SP-C. The Journal of cell biology 89 16449190
2005 Interaction between TFF1, a gastric tumor suppressor trefoil protein, and TFIZ1, a brichos domain-containing protein with homology to SP-C. Biochemistry 86 15924415
1991 Effects of maternal dexamethasone on expression of SP-A, SP-B, and SP-C in the fetal rat lung. American journal of respiratory cell and molecular biology 86 2015097
2006 Reactive oxygen species inactivation of surfactant involves structural and functional alterations to surfactant proteins SP-B and SP-C. Biophysical journal 82 16443649
2014 A non-BRICHOS SFTPC mutant (SP-CI73T) linked to interstitial lung disease promotes a late block in macroautophagy disrupting cellular proteostasis and mitophagy. American journal of physiology. Lung cellular and molecular physiology 81 25344067
1997 Combinations of fluorescently labeled pulmonary surfactant proteins SP-B and SP-C in phospholipid films. Biophysical journal 81 9168039
1993 Lung surfactant proteins, SP-B and SP-C, alter the thermodynamic properties of phospholipid membranes: a differential calorimetry study. Biochemistry 77 8422370
2010 Identification of early interstitial lung disease in an individual with genetic variations in ABCA3 and SFTPC. Chest 75 20371530
1993 Differential glucocorticoid regulation of the pulmonary hydrophobic surfactant proteins SP-B and SP-C. American journal of respiratory cell and molecular biology 75 8427712
1992 Lipid mixing is mediated by the hydrophobic surfactant protein SP-B but not by SP-C. Biochimica et biophysica acta 75 1390835
1994 Dynamic surface properties of pulmonary surfactant proteins SP-B and SP-C and their mixtures with dipalmitoylphosphatidylcholine. Biochemistry 70 7993894
1990 Interaction between perdeuterated dimyristoylphosphatidylcholine and low molecular weight pulmonary surfactant protein SP-C. Biochemistry 68 2383558
1992 Differential sensitivity to fibrinogen inhibition of SP-C- vs. SP-B-based surfactants. The American journal of physiology 66 1550251
2015 Genotype alone does not predict the clinical course of SFTPC deficiency in paediatric patients. The European respiratory journal 63 25657025
1996 Transcriptional regulation of human pulmonary surfactant proteins SP-B and SP-C by glucocorticoids. American journal of respiratory cell and molecular biology 63 8652188
2004 FGF-10 induces SP-C and Bmp4 and regulates proximal-distal patterning in embryonic tracheal epithelium. American journal of physiology. Lung cellular and molecular physiology 62 15531758
1991 The pulmonary surfactant protein C (SP-C) precursor is a type II transmembrane protein. The Biochemical journal 59 1859376
2008 rtTA toxicity limits the usefulness of the SP-C-rtTA transgenic mouse. Developmental biology 57 19013447
1999 Effect of hydrophobic surfactant peptides SP-B and SP-C on binary phospholipid monolayers. I. Fluorescence and dark-field microscopy. Biophysical journal 57 10423435
1992 Localization of surfactant-associated protein C (SP-C) mRNA in fetal rabbit lung tissue by in situ hybridization. American journal of respiratory cell and molecular biology 57 1540386
1994 SP-A, SP-B, and SP-C in surfactant subtypes around birth: reexamination of alveolar life cycle of surfactant. The American journal of physiology 54 8179020
2003 A synthetic surfactant based on a poly-Leu SP-C analog and phospholipids: effects on tidal volumes and lung gas volumes in ventilated immature newborn rabbits. Journal of applied physiology (Bethesda, Md. : 1985) 52 12897027
1994 Pulmonary surfactant proteins SP-B and SP-C in spread monolayers at the air-water interface: III. Proteins SP-B plus SP-C with phospholipids in spread monolayers. Biophysical journal 50 8038387
2013 Hydrophobic pulmonary surfactant proteins SP-B and SP-C induce pore formation in planar lipid membranes: evidence for proteolipid pores. Biophysical journal 49 23332067
2012 SP-B and SP-C containing new synthetic surfactant for treatment of extremely immature lamb lung. PloS one 49 22808033
2010 Synthetic surfactant based on analogues of SP-B and SP-C is superior to single-peptide surfactants in ventilated premature rabbits. Neonatology 49 20110733
2009 Pulmonary surfactant protein SP-C counteracts the deleterious effects of cholesterol on the activity of surfactant films under physiologically relevant compression-expansion dynamics. Biophysical journal 49 19917227
2000 Human SP-C gene sequences that confer lung epithelium-specific expression in transgenic mice. American journal of physiology. Lung cellular and molecular physiology 49 10781423
1995 Conformational flexibility of pulmonary surfactant proteins SP-B and SP-C, studied in aqueous organic solvents. Biochimica et biophysica acta 49 7893740
2002 Biosynthesis of surfactant protein C (SP-C). Sorting of SP-C proprotein involves homomeric association via a signal anchor domain. The Journal of biological chemistry 48 11907042
1996 Overexpression of surfactant protein SP-A, SP-B, and SP-C mRNA in rat lungs with lipopolysaccharide-induced injury. Laboratory investigation; a journal of technical methods and pathology 48 8569184
1992 Structure and functions of a dimeric form of surfactant protein SP-C: a Fourier transform infrared and surfactometry study. Chemistry and physics of lipids 48 1486663
2011 A combined action of pulmonary surfactant proteins SP-B and SP-C modulates permeability and dynamics of phospholipid membranes. The Biochemical journal 45 21679160
2018 Synthetic surfactants with SP-B and SP-C analogues to enable worldwide treatment of neonatal respiratory distress syndrome and other lung diseases. Journal of internal medicine 44 30357986
2002 An ELISA technique for quantification of surfactant apoprotein (SP)-C in bronchoalveolar lavage fluid. American journal of respiratory and critical care medicine 44 11850338
1992 An antibody with specificity for surfactant protein C precursors: identification of pro-SP-C in rat lung. American journal of respiratory cell and molecular biology 44 1389209
2018 Genetic Association of Pulmonary Surfactant Protein Genes, SFTPA1, SFTPA2, SFTPB, SFTPC, and SFTPD With Cystic Fibrosis. Frontiers in immunology 42 30333828
2010 Surfactant protein C gene (SFTPC) mutation-associated lung disease: high-resolution computed tomography (HRCT) findings and its relation to histological analysis. Pediatric pulmonology 42 20658481
1996 Roles of SP-A, SP-B, and SP-C in modulation of lipid uptake by pulmonary epithelial cells in vitro. The American journal of physiology 42 8772529
1991 Lung surfactant protein SP-C from human, bovine, and canine sources contains palmityl cysteine thioester linkages. The American journal of physiology 41 1872406
2021 Heterogeneity in Human Induced Pluripotent Stem Cell-derived Alveolar Epithelial Type II Cells Revealed with ABCA3/SFTPC Reporters. American journal of respiratory cell and molecular biology 38 34101541
2002 Kinetics of phospholipid insertion into monolayers containing the lung surfactant proteins SP-B or SP-C. European biophysics journal : EBJ 38 12046897
2008 Foxp2 inhibits Nkx2.1-mediated transcription of SP-C via interactions with the Nkx2.1 homeodomain. American journal of respiratory cell and molecular biology 37 18239190
2003 Deacylated pulmonary surfactant protein SP-C transforms from alpha-helical to amyloid fibril structure via a pH-dependent mechanism: an infrared structural investigation. Biophysical journal 37 14507705
1993 Lipid effects on aggregation of pulmonary surfactant protein SP-C studied by fluorescence energy transfer. Biochemistry 36 8373758
1992 Surfactant protein C: hormonal control of SP-C mRNA levels in vitro. The American journal of physiology 36 1319687
1993 Full length synthetic surfactant proteins, SP-B and SP-C, reduce surfactant inactivation by serum. Biochimica et biophysica acta 35 8323972
2010 Palmitoylation of pulmonary surfactant protein SP-C is critical for its functional cooperation with SP-B to sustain compression/expansion dynamics in cholesterol-containing surfactant films. Biophysical journal 34 21081071
2002 Deficiency of SP-B reveals protective role of SP-C during oxygen lung injury. Journal of applied physiology (Bethesda, Md. : 1985) 34 11796659
2002 Effect of hydrophobic surfactant protein SP-C on binary phospholipid monolayers. Molecular machinery at the air/water interface. Biophysical chemistry 34 12408937
2001 Lipid-protein interactions of hydrophobic proteins SP-B and SP-C in lung surfactant assembly and dynamics. Pediatric pathology & molecular medicine 33 11699574
1999 Palmitoylation of lung surfactant protein SP-C alters surface thermodynamics, but not protein secondary structure or orientation in 1,2-dipalmitoylphosphatidylcholine langmuir films. Biochimica et biophysica acta 33 9889301
2016 Effect of Lung Surfactant Protein SP-C and SP-C-Promoted Membrane Fragmentation on Cholesterol Dynamics. Biophysical journal 32 27760357
2016 Surfactant Protein C-associated interstitial lung disease; three different phenotypes of the same SFTPC mutation. Italian journal of pediatrics 31 26925580
2004 The N-terminal segment of pulmonary surfactant lipopeptide SP-C has intrinsic propensity to interact with and perturb phospholipid bilayers. The Biochemical journal 31 14514353
2003 Effect of hydrophobic surfactant proteins SP-B and SP-C on binary phospholipid monolayers: II. Infrared external reflectance-absorption spectroscopy. Biophysical journal 31 12524286
1999 Biophysical activity of an artificial surfactant containing an analogue of surfactant protein (SP)-C and native SP-B. The Biochemical journal 30 10191270
2008 Effect of acylation on the interaction of the N-Terminal segment of pulmonary surfactant protein SP-C with phospholipid membranes. Biochimica et biophysica acta 29 18339301
2005 Interaction of the N-terminal segment of pulmonary surfactant protein SP-C with interfacial phospholipid films. Biochimica et biophysica acta 29 16002041
2003 Effects of oligomerization and secondary structure on the surface behavior of pulmonary surfactant proteins SP-B and SP-C. Biophysical journal 29 12609896
1996 The surface properties of chemically synthesized peptides analogous to human pulmonary surfactant protein SP-C. Biological & pharmaceutical bulletin 29 8913491
1995 Structural and functional importance of the C-terminal part of the pulmonary surfactant polypeptide SP-C. European journal of biochemistry 29 7744069
2013 SFTPC mutations cause SP-C degradation and aggregate formation without increasing ER stress. European journal of clinical investigation 28 23701443
1998 Nicotine stimulates branching and expression of SP-A and SP-C mRNAs in embryonic mouse lung culture. The American journal of physiology 28 9458815
2018 Homo- and hetero-oligomerization of hydrophobic pulmonary surfactant proteins SP-B and SP-C in surfactant phospholipid membranes. The Journal of biological chemistry 27 29700110
2011 Rapamycin Regulates Bleomycin-Induced Lung Damage in SP-C-Deficient Mice. Pulmonary medicine 27 21660239
1998 Rotational dynamics of spin-labelled surfactant-associated proteins SP-B and SP-C in dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylglycerol bilayers. Biochimica et biophysica acta 27 9858708
1995 Characterization of a dimeric canine form of surfactant protein C (SP-C). Biochimica et biophysica acta 27 7857973
2006 Production and characterisation of recombinant forms of human pulmonary surfactant protein C (SP-C): Structure and surface activity. Biochimica et biophysica acta 26 16631109
1994 Differential expressions of surfactant protein SP-A, SP-B, and SP-C mRNAs in rats with streptozotocin-induced diabetes demonstrated by in situ hybridization. American journal of respiratory cell and molecular biology 26 7917308
2014 Synthetic surfactant containing SP-B and SP-C mimics is superior to single-peptide formulations in rabbits with chemical acute lung injury. PeerJ 25 24883253
2014 Palmitoylation as a key factor to modulate SP-C-lipid interactions in lung surfactant membrane multilayers. Biochimica et biophysica acta 25 25306965
1996 Characterization of poly-leucine substituted analogues of the human surfactant protein SP-C. Biological & pharmaceutical bulletin 25 8996637

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